Insulin regulates blood glucose by
(a) decreasing glucose outflow from the liver and
(b) increasing glucose uptake in peripheral tissues, e.g. muscles and adipose tissues.
Insulin exerts these effects by interacting with the insulin receptor present on most cells. The sensitivity to insulin is a function of the number of insulin receptors of individual cells. This number is decreased or "downregulated" by insulin, i.e. high concentrations of insulin secondarily lead to relative insulin resistance. Conditions characterized by an excessive endogenous insulin secretion are obesity, type 2 diabetes, hyperlipidemia type IV of Fredricksen. In type 1 diabetes (juvenile diabetes mellitus, insulin dependent) insulin resistance is the consequence of the peripheral administration of insulin so that the glucose homeostatic function of the liver is impaired and peripheral glucose uptake excessive. The treatment of obesity, type 2 diabetes (non-insulin dependent) and hyperlipidemia consists primarly of dietary measures, i.e. caloric restriction. Patient compliance is notoriously bad and there is a need for new and better therapeutic measures. In insulin treated type 1 diabetes, hyperinsulinemia results from the fact that insulin is delivered s.c. rather than intraportally so that the delivered insulin reaches peripheral tissues first rather than after passage through the liver. There is a need to overcome the drawbacks of excessive insulin secretion and hyperinsulinemia.
Insulin-like growth factor I (IGF I) has been shown to lower blood glucose in man after intravenous bolus injection (1). Growth-promoting actions of IGF I have been documented in several metabolic conditions which have low IGF I levels in common, e.g. hypophysectomized rats (2) (5), diabetic rats (3) and Snell dwarf mice (4).
It has now been found that prolonged infusions of IGF I inhibit growth hormone secretion. In addition, blood glucose and peripheral levels of insulin remained constant but the levels of the C-peptide fell markedly indicating that endogenous insulin secretion was reduced. During IGF I infusion triglyceride, cholesterol and LDL-cholesterol tended to decrease while HDL-cholesterol increased. These findings show that during IGF I infusions insulin secretion is decreased and that IGF I helps to maintain glucose homeostasis with considerably less insulin thus overcoming the drawbacks of hyperinsulinemia. There are at least two mechanisms of action of IGF 1: As shown in the bolus experiments, IGF I leads to hypoglycemia by increasing glucose uptake primarily of muscle. It is conceivable that IGF I infusions may also facilitate glucose uptake by muscle and this effect is dose related. The second, so far unknown effect has to do with insulin degradation.
So far there exists no report on the inhibition of insulin secretion during administration of IGF I. It is foreseen that the administration of IGF I leads to a diminished need of insulin thereby preventing the secondary effects of hyperinsulinemia.